System and method to regulate ultrafiltration

ABSTRACT

A medical device system including a physiological sensor and ultrafiltration unit senses a physiological signal in a patient and computes a fluid status measurement of the patient using the physiological signal. Ultrafiltration therapy is delivered to the patient according to a therapy delivery control parameter established in response to the fluid status measurement.

TECHNICAL FIELD

The disclosure relates generally to implantable medical devices and, inparticular, to an implantable medical device (IMD) system and associatedmethod for regulating ultrafiltration therapy.

BACKGROUND

In the early stages of heart failure, compensatory mechanisms occur inresponse to the heart's inability to pump a sufficient amount of blood.One compensatory response is an increase in filling pressure of theheart. The increased filling pressure increases the volume of blood inthe heart, allowing the heart to eject a larger volume of blood on eachheart beat. Increased filling pressure and other compensatory mechanismscan initially occur without overt heart failure symptoms.

The mechanisms that initially compensate for insufficient cardiacoutput, however, lead to heart failure decompensation as the heartcontinues to weaken. The weakened heart can no longer pump effectivelycausing increased filling pressure to lead to chest congestion (thoracicedema) and heart dilation, which further compromises the heart's pumpingfunction. The patient begins the “vicious cycle” of heart failure whichgenerally leads to hospitalization.

Typically, therapy for a patient hospitalized for acute decompensatedheart failure includes early introduction of intravenous infusion ofdiuretics or vasodilators to clear excess fluid retained by the patient.A new therapy being introduced to remove excess fluid volume frompatients with congestive heart failure and/or renal dysfunction isultrafiltration. Ultrafiltration involves filtering a patient's blood toremove excess fluid then returning the filtered blood back to thepatient. Ultrafiltration methods currently in use require manual controlof the ultrafiltration unit. A challenge faced in deliveringultrafiltration therapy is knowing when and how much fluid to remove andthe rate at which to remove fluid. Removing fluid too quickly maydeplete intravascular fluid volume at a rate faster than edematous fluidcan be reabsorbed from the tissues. Removing fluid too slowly may allowsymptoms and the adverse affects of high filling pressures to persistlonger than necessary. If the total fluid volume removed isinsufficient, patient symptoms may not be fully alleviated, oralleviated symptoms may return quickly. Overdiuresis can occur if toomuch fluid is removed. Overdiuresis may require fluid to be administeredto the patient to increase the patient's fluid volume status. Removingand adding fluid can pose additional burden on the kidneys, which mayalready be compromised due to renal insufficiency. A need remains,therefore, for a system and method for use in regulating ultrafiltrationtherapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of an implantable medical device (IMD)coupled to a lead positioned within a heart in a patient's body.

FIG. 2 is a functional block diagram of a medical device systemincluding at least an implantable physiological sensor and anultrafiltration unit.

FIG. 3 is a functional block diagram of one embodiment of IMD.

FIG. 4 is a flow chart of a method for regulating ultrafiltrationtherapy.

FIG. 5 is an illustrative time-based plot of a fluid status measurementas it might vary over the course of periodic ultrafiltration therapysessions.

FIG. 6 is a time-based plot of a fluid status measurement during anultrafiltration therapy session.

FIG. 7 is a flow chart of an alternative method for regulatingultrafiltration therapy.

DETAILED DESCRIPTION

In the following description, references are made to illustrativeembodiments. It is understood that other embodiments may be utilizedwithout departing from the scope of the invention. For purposes ofclarity, the same reference numbers are used in the drawings to identifysimilar elements.

As used herein, the term “controller” refers to an application specificintegrated circuit (ASIC), an electronic circuit, a processor (shared,dedicated, or group) and memory that execute one or more software orfirmware programs, a combinational logic circuit, or other suitablecomponents that provide the described functionality.

FIG. 1 is a schematic diagram of an implantable medical device (IMD) 10coupled to a lead 14 positioned within a heart 8 in a patient's body 6.IMD 10 is capable of monitoring at least one physiological signal fromwhich variables useful in monitoring a patient's fluid status can bederived. IMD 10 may or may not be provided with therapy deliverycapabilities. IMD 10 may correspond to a variety of implantable medicaldevices including a cardiac pacemaker, implantable cardioverterdefibrillator, implantable hemodynamic monitor, a drug pump, aneurostimulator or the like. Accordingly, IMD 10 may be coupled toadditional leads and/or catheters operatively positioned relative to thepatient's heart 8 or other body tissues for deployingstimulating/sensing electrodes, other physiological sensors, and/or drugdelivery ports. While lead 14 is shown terminated within the rightventricle of the patient's heart, it is recognized that lead 14 may beconfigured as a transvenous lead that extends into other heart chambersor blood vessels for positioning electrodes and/or physiological sensorsin a desired location.

In one embodiment, IMD 10 corresponds to an implantable hemodynamicmonitor capable of sensing and recording ECG signals, intracardiac rightventricular pressure signals, and transthoracic impedance signals. IMD10 stores the sensed signals and further derives fluid statusmeasurements from the sensed signals for monitoring the fluid volumestatus of the patient. ECG signals are sensed using one or moreelectrodes 18 carried by lead 14 or using alternative electrodes (notshown) incorporated on the housing 12 of IMD 10. Housing 12 enclosescircuitry (not shown in FIG. 1) included in IMD 10 for controlling andperforming device functions and processing sensed signals.

An electrode 18 carried by lead 14 is used with the IMD housing 12 formeasuring a transthoracic impedance for use in monitoring intrathoracicfluid status. As used herein, “transthoracic” impedance refers to anyimpedance measurement across a portion of the thorax, including across aportion of the heart, lungs and/or pulmonary vascular bed. Inalternative embodiments, one or more lead-based electrodes and/or one ormore subcutaneously placed electrodes, incorporated on IMD housing 12 orcarried by a subcutaneously extending lead, may be used to measuretransthoracic impedance across a portion of the thoracic cavity, heartand/or lungs for use in deriving a variable useful in monitoring fluidstatus.

Transthoracic electrical impedance decreases as the fluid in the chestincreases. Transthoracic impedance decreases with heart failuredecompensation as fluid accumulates in the chest and the heart and bloodvessels dilate due to elevated right heart filling pressures andinsufficient cardiac ejection. As such, transthoracic impedancemeasurements may be used in deriving a fluid status measurement usefulin controlling ultrafiltration therapy administered to a patient.

As used herein, a “fluid status measurement” is a measurement or indexderived from a physiological sensor signal and is correlated to theblood volume of the patient or edemic state of the patient. As such aworsening fluid status measurement is a measurement that corresponds toincreased fluid retention by the patient corresponding to hypervolemiaand/or edema. A hypervolemic volume state of the patient occurs when thevolume status exceeds the optivolemic state and corresponds to a fluidstatus measurement that crosses an optivolemic level of the fluid statusmeasurement, which may be an increasing or decreasing change in thefluid status measurement depending on the particular measurement beingused. For example, intraventricular pressure would increase with fluidoverload and would decrease in a state of overdiuresis or hypovolemia. Atransthroracic impedance would decrease with fluid overload and increasewith overdiruesis or hypovolemia. Other fluid status measurements may bederived from an oxygen sensor or a blood chemistry sensor measuring, forexample, blood urea nitrogen, serum creatinine, serum electrolytesincluding calcium and magnesium, blood glucose, or thyroid stimulatinghormone, or any combination of the foregoing measurements.

Lead 14 is further provided with a pressure sensor 16. Pressure sensor16 is used for monitoring pressure within the right ventricle (RV) foruse in deriving pressure-related fluid status measurements. The RVpressure signal can be used directly or used to determine an estimatedpulmonary artery diastolic (ePAD), pressure which increases during heartfailure decompensation. While ePAD pressure is one useful variable thatcan be derived from a RV pressure signal, numerous otherpressure-related variables may be useful in monitoring a fluid status.Furthermore, pressure signals obtained at other locations in the heartor vasculature may be used for deriving a fluid status measurement.

Any blood pressure measurement acquired at any measurement site that iscorrelated to cardiac filling pressure may be used since increasedcardiac filling pressure reflects a hypervolemic state and leads topulmonary edema. Among the pressure measurements that may be used as ameasure of cardiac filling pressure, i.e. to derive a fluid statusmeasurement, are left ventricular end diastolic pressure, left atrialpressure, pulmonary venous pressure, pulmonary arterial diastolicpressure, right ventricular ePAD, right ventricular diastolic pressure,right atrial pressure, and central venous pressure. While the abovelisted measurements are all intravascular measurements made within thethorax (intrathoracic), it is also understood that other extrathoracicvenous pressure measurements, such as hepatic venous pressure or jugularvenous pressure, could also be used to indicate the patient's volumestatus for the purposes of controlling ultrafiltration.

IMD 10 is capable of bidirectional communication with an external device26 via bidirectional telemetry link 28. Device 26 may be embodied as aprogrammer, typically located in a hospital or clinic, used to programthe operating mode and various operational variables of IMD 10 andinterrogate IMD 10 to retrieve data stored by IMD 10. Device 26 mayalternatively be embodied as a home monitor used to retrieve data fromthe IMD 10 and may be used to program IMD 10 but may have limitedprogramming functionality as compared to a hospital or clinicprogrammer. Data stored and retrieved from IMD 10 may include datarelated to IMD function determined through automated self-diagnostictests as well as physiological data acquired by IMD 10 using pressuresensor 16 and electrode(s) 18.

External device 26 is further shown in communication with a centraldatabase 24 via communication link 30, which may be a wireless orhardwired link. Programming data and interrogation data may betransmitted via link 30. Central database 24 may be a centralizedcomputer, web-based or other networked database used by a clinician forremote monitoring and management of patient 6. It is recognized thatother external devices, such as other physiological monitoring devicesor other types of programming devices, may be used in conjunction withIMD 10 and incorporate portions of the methods described herein.

An ultrafiltration unit 32 is coupled to the patient 6 via catheters 34for removing excess fluid from the patient. The ultrafiltration unit 32passes the patient's blood through a filter to remove fluid then returnsthe blood, with fluid removed, to the patient 6. In some embodiments,ultrafiltration unit 32 is enabled for telemetric communication with IMD10, programmer or monitor 26 and/or central database 24. Ultrafiltrationunit 32 may receive data, such as ultrafiltration control parameters,fluid status data for setting delivery control parameters, ornotifications relating to the patient's fluid status. In this way,automated or semi-automated control of ultrafiltration therapy may beachieved using fluid status measurements obtained by IMD 10.

In other embodiments, ultrafiltration unit 32 is manually adjusted inresponse to fluid status measurements and notifications provided by IMD10, which may be transmitted for viewing on an external display 36 by anurse or clinician, or, in the case of home ultrafiltration, by thepatient. Display 36 is shown implemented on programmer 26 but mayalternatively or additionally be associated with central database 24.When ultrafiltration unit 32 is enabled for communication with IMD 10,programmer 26 or central database 24, ultrafiltration unit 32 mayinclude a display (not shown) for displaying data received from the IMDsystem relating to the patient's fluid status. For example, fluid statusmeasurements and/or recommended ultrafiltration control parameters maybe received and stored on display 36 or another display incorporated inultrafiltration unit 32. The remote transmission of fluid status data toa central database 24 so that it can be reviewed by an expert clinicianallows the clinician to remotely set a range of ultrafiltration controlparameters allowed to be used by the ultrafiltration unit 32.

Ultrafiltration unit 32 is an external unit that may be located in ahospital or clinic, a portable unit in a patient's home, or a wearableunit used by the patient in or away from a hospital or clinic. In otherembodiments, an implantable ultrafiltration unit 40 may be used todeliver the ultrafiltration therapy. The implantable unit 40, like theexternal unit 32, would be coupled to the patient's vasculature usingcatheters 42 for receiving a volume of the patient's blood, filteringthe blood to remove fluid, then returning the filtered blood back to thepatient's vasculature system.

The implantable ultrafiltration unit 40 may be in wireless communicationwith IMD 10 for receiving data relating to the patient's fluid status.The fluid status measurements received from IMD 10 would be used by acontroller in IMD 10 or in the ultrafiltration unit 40 for establishingultrafiltration control parameters used by ultrafiltration unit 40.Ultrafiltration unit 40 may alternatively be configured for wirelesscommunication with an external programmer, such as programmer 26 oranother dedicated programmer, or central database 24. The externalprogrammer or central database is provided with a controller forestablishing ultrafiltration control parameters using the fluid statusmeasurements obtained by IMD 10. The external programmer or centraldatabase either displays the recommended control parameters or transmitsthe control parameters to the implantable unit 40. Ultrafiltration unit40 may then be programmed manually or automatically by an externalprogrammer using control parameters established based on fluid statusmeasurements from IMD 10. It is understood that additional communicationlinks would be provided as needed between implantable unit 40 andexternal components 26 and 24 and are not shown explicitly in FIG. 1 forthe sake of clarity.

In still other embodiments, it is contemplated to include aphysiological sensor in, or coupled to, implantable ultrafiltration unit40 for sensing a signal that can be used to compute a fluid statusmeasurement. A controller in the ultrafiltration unit establishesultrafiltration control parameters used for controlling ultrafiltrationtherapy in a closed loop manner within the implanted unit 40.

Various methods described herein for determining the fluid status of apatient using one or more physiological signals sensed by an implantablesensor, establishing ultrafiltration control parameters based on thephysiological signals, and setting the control parameters in theultrafiltration unit 32 or 40 may be implemented in one or more of theIMD system components shown in FIG. 1, namely IMD 10, external device26, central database 24, and ultrafiltration unit 32 or 40. Thedescribed functionality may include any combination of hardware,firmware and/or software.

FIG. 2 is a functional block diagram of a medical device system 100including at least an implantable sensor for sensing physiologicalsignals and an ultrafiltration unit for delivering ultrafiltrationtherapy. Physiological sensor 102 provides signals to a processor 104which computes a fluid status measurement using the sensed signals. Acontroller 108 receives the computed fluid status measurements anddetermines control parameters for ultrafiltration therapy delivery 110.Control parameters may be set or adjusted automatically to controlultrafiltration therapy delivery 110. To facilitate manual adjustment ofcontrol parameters, a user interface 114 and display 112 is provided todisplay data relating to fluid status measurements and/or establishedcontrol parameters and allow a user to enter commands or set controlparameters accordingly. The user interface 114 and the display 112 maybe integrated in a graphical user interface and may be a singleinterface used with a controller 108 or with ultrafiltration delivery110. Display 112 may also be used to display notifications to a patientor clinician to indicate a need for ultrafiltration therapy or a need toadjust or terminate ultrafiltration.

In various embodiments, controller 108 may be implemented in theultrafiltration unit, in the IMD, in a central database, or in anexternal programmer or home monitor or across any of these components.The controller 108 is adapted to receive fluid status measurement dataand establish ultrafiltration control parameters in response to thedata. The controller 108 may or may not be adapted to automatically setestablished control parameters in the ultrafiltration unit. Userintervention may be required in transferring fluid status measurementdata to the controller and/or transferring established controlparameters to the ultrafiltration therapy delivery 110 to set thecontrol parameters and enable or disable ultrafiltration.

The functionality shown in FIG. 2 can be implemented in a single device,such as within an implantable ultrafiltration unit 40, including aphysiological sensor and processing and control circuitry, ordistributed across the various system components shown in FIG. 1, inwhich case it is understood that necessary communication modules areincorporated for transmitting data between system components as neededautomatically or with user intervention.

FIG. 3 is a functional block diagram of one embodiment of IMD 10. IMD 10generally includes timing and control circuitry 52 and a control unitthat may employ microprocessor 54 or a digital state machine for timingsensing and therapy delivery functions (when present) in accordance witha programmed operating mode. Microprocessor 54 and associated memory 56are coupled to the various components of IMD 10 via a data/address bus55.

IMD 10 may include therapy delivery module 50 for delivering a therapyin response to determining a need for therapy, e.g., based on sensedphysiological signals. Therapy delivery module 50 may provide drugdelivery therapies or electrical stimulation therapies, such as cardiacpacing or anti-arrhythmia therapies. In some embodiments, IMD 10 mayinclude ultrafiltration therapy capabilities and would then be coupledto catheters for receiving and pumping blood across a filter andreturning blood to the patient's vasculature. Therapies are delivered bymodule 50 under the control of timing and control circuitry 52.

Therapy delivery module 50 may be coupled to two or more electrodes 68via an optional switch matrix 58. Switch matrix 58 may be used forselecting which electrodes and corresponding polarities are used fordelivering electrical stimulation pulses. Electrodes 68 may correspondto any electrodes incorporated in IMD housing 12 or other lead-basedelectrodes, including electrode(s) 18 carried by lead 14 (shown in FIG.1).

As discussed above, IMD 10 may be configured to measure impedancesignals for deriving a fluid status measurement. As such, selectedelectrodes 68 are coupled to impedance measuring module 80 for providingan impedance measurement drive signal along an excitation path. Thevoltage is then measured across the measuring electrodes allowing theimpedance across the measurement path to be computed from the knowndrive signal and the measured voltage. Impedance measurement methods andassociated apparatus are generally disclosed in PCT Publication WO2008/014078 (Stylos), incorporated herein by reference in its entirety.

IMD 10 is additionally coupled to one or more sensors 70 used to monitorphysiological signals. Physiological sensors 70 include pressure sensor16 as shown in FIG. 1 and may further include sensors responsive tomotion, flow, blood chemistry (including but not limited to blood ureanitrogen, serum creatinine, serum electrolytes including calcium andmagnesium, blood glucose, and thyroid stimulating hormone), patientactivity, patient posture, oxygen, temperature or other physiologicalsensors used in conjunction with implantable medical devices.Physiological sensors may be carried by leads extending from IMD 10,incorporated in or on the IMD housing 12, or embodied as wirelesssensors in telemetric communication with IMD 10.

Sensor signals are received by a sensor interface 62 which may provideinitial amplification, filtering, rectification, or other signalconditioning. Sensor signals may then be provided to signal processingcircuitry 60 for analog-to-digital conversion, averaging, integration,peak detection or other signal processing required for a particularapplication to derive desired signal features used to compute fluidstatus measurements. Microprocessor 54 receives the processed sensorsignals for detecting physiological events or conditions. In particular,signals from pressure sensor 16 are processed by signal processor 60and/or microprocessor 54 for deriving a fluid status measurement from apressure signal.

A fluid status monitoring algorithm may be stored in memory 56 andexecuted by microprocessor 54 with input received from electrodes 68,physiological sensors 70, signal processor 60 and impedance measuringmodule 80. Microprocessor 54 in conjunction with memory 56 may operateas a control unit for executing software-implemented algorithms formonitoring fluid status using an impedance variable and/or a pressurevariable derived by processor 60, impedance module 80, and/or bymicroprocessor 54 using sensed signals. The algorithms stored in memory56 are retrieved by microprocessor 54 as needed. In alternativeembodiments, functionality described herein may be implemented usingdedicated hardware and/or firmware.

Fluid status data may be stored in memory 56 for use in diagnosing ormonitoring the patient, determining the need for delivering a therapyunder control of the operating system, or a separate ultrafiltrationunit. Memory 56 may store a variety of programmed parameter values thatare used by microprocessor 54 for determining the need for therapy andfor establishing therapy control parameters. Memory 56 may also be usedfor storing data compiled from sensed physiological signals and/orrelating to device operating history for telemetry out on receipt of aretrieval or interrogation instruction.

IMD 10 further includes telemetry circuitry 64 and antenna 65.Programming commands or data are transmitted during uplink or downlinktelemetry between IMD telemetry circuitry 64 and external telemetrycircuitry included in a programmer or monitoring unit such as programmer26 as shown in FIG. 1.

Alert module 74 generates patient or clinician notifications in responseto detecting various patient-related or device-related conditions. Anotification may be an audible sound or a message transmitted viatelemetry 64 to an external device. A notification may be generated bymodule 74 in response to fluid status measurements determined by IMD 10.In particular, a notification may be generated by IMD 10 when fluidstatus measurements monitored by IMD 10 indicate a need to start, stopor adjust ultrafiltration therapy.

FIG. 4 is a flow chart 200 of one embodiment of a method for regulatingultrafiltration therapy. Flow chart 200 is intended to illustrate thefunctional operation of a medical device system, and should not beconstrued as reflective of a specific form of software or hardwarenecessary to practice the embodiments described herein. It is believedthat the particular form of software will be determined primarily by theparticular system architecture employed in the device system and by theparticular sensing and therapy delivery methodologies employed by thesystem. Providing software to accomplish the described functionality inthe context of any modern implantable medical device system, given thedisclosure herein, is within the abilities of one of skill in the art.

Methods described in conjunction with flow charts presented herein maybe implemented in a computer-readable medium that includes instructionsfor causing a programmable processor to carry out the methods described.A “computer-readable medium” includes but is not limited to any volatileor non-volatile media, such as a RAM, ROM, CD-ROM, NVRAM, EEPROM, flashmemory, and the like. The instructions may be implemented as one or moresoftware modules, which may be executed by themselves or in combinationwith other software.

At block 202, a physiological signal is sensed using an implantablephysiological sensor for use in monitoring a patient's fluid status. Thesignal may be, without limitation, a blood pressure signal and/or animpedance signal as described previously. At block 204, fluid statusmeasurements are computed and stored by the IMD, according to aprogrammed monitoring algorithm, using the sensed physiologicalsignal(s). For example, hourly, daily, weekly or other periodicmeasurements may be acquired. The frequency of fluid status measurementacquisition will depend in part on the patient condition. For example, apatient suffering from renal dysfunction may be monitored at least dailyto allow daily fluctuations in fluid status to be assessed. In a heartfailure patient that experiences fluid overload infrequently, a weeklyassessment may be adequate.

At block 206, a target range for the fluid status measurement isdetermined. The target range may be user-defined input by a clinicianand stored in the IMD or a controller used to establish ultrafiltrationcontrol parameters. Alternatively, the target range is computed by theIMD or a controller using the patient's fluid status measurement historyretrieved from IMD memory. The target range may be a pressure range, forexample corresponding to an intracardiac blood pressure, ePAD pressure,central venous pressure, or other pressure measurement. In otherembodiments, the target range may correspond to a transthoracicimpedance measurement. In still other embodiments, the target range maybe defined as a range of an index computed using a combination of two ormore different fluid status measurements obtained by the IMD, such asany combination of an intracardiac pressure, a transthoracic impedance,blood chemistries, oxygen, flow or other physiologic sensor signals.

The target range may be computed using stored fluid status measurementsby the IMD processor, by a processor included in an external programmeror home monitor, by a central database used for remote patientmonitoring, or by a controller incorporated in the ultrafiltration unitor separately from the ultrafiltration unit for establishingultrafiltration control parameters. The target range is generallyassociated with an optivolemic level or range of the fluid statusmeasurement at which the patient is expected to be stable with reduced(or no) symptoms associated with fluid overload.

The target range may be determined and stored prospectively at block206. Alternatively, the target range may be determined at the time thata need for ultrafiltration therapy is recognized as indicated at block205. For example, if a patient is hospitalized for symptoms associatedwith fluid overload, a clinician may prescribe ultrafiltration therapy.A clinician may interrogate the IMD using an external programmer toretrieve fluid status measurements. The fluid status measurement trendeddata may then be used by a controller to compute a target range for thefluid status measurement to be achieved by the ultrafiltration therapy.As will be described further below, the target range may be used inother embodiments for determining the need for ultrafiltration therapy.

At block 208 the currently measured fluid status measurement is comparedto the ultrafiltration target range by the controller. This comparisonis used to establish an ultrafiltration control parameter setting atblock 210. For example, the control parameter may be a flow rate atwhich blood flows through the ultrafiltration system. A flow ratesetting may be established according to how far a current fluid statusmeasurement is out of the target range. In other words, the flow rate isadjusted in proportion to a difference between the fluid statusmeasurement and a boundary of the target range, which may be the nearestor furthest boundary of the target range. The difference between a fluidstatus measurement and a boundary of the target range can be referred toas a “control signal” in that this difference is used to establishultrafiltration control parameters. Hierarchal levels of flow rate maybe set based on hierarchal levels or percentiles of the fluid statusmeasurement values relative to the target range, i.e. the “controlsignal”. In one illustrative example, the flow rate may be set to ahigh, medium or low rate depending on whether the fluid statusmeasurement exceeds a predetermined high threshold above (or below inthe case of an impedance measurement) the target range (a high controlsignal), a medium threshold outside the target range (a moderate controlsignal), or a low threshold outside the target range (a low controlsignal).

The ultrafiltration therapy is started at block 212 using theestablished control parameter setting. It is recognized that one or morecontrol parameters may be established and set based on a current fluidstatus measurement and target range. During the ultrafiltration therapy,the fluid status measurement is monitored by the IMD at block 214. Fluidstatus monitoring during ultrafiltration may be performed continuouslyor on a periodic basis such as every minute, every hour, or at anotherperiodic interval which may be a programmable interval.

If a target level within the target range is reached at block 216, theultrafiltration therapy is stopped at block 222. A target level may beany level within the target range including one of the target rangeboundaries. For example, the target level may be set to a target rangeboundary corresponding to a “best” fluid status, i.e. a lower boundaryfor a pressure-based measurement and an upper boundary for animpedance-based measurement, or another level within the target rangecorresponding to an optimal fluid status measurement. By performingultrafiltration until a target level within the target range or afurthest boundary is reached rather than just until the fluid statusmeasurement reaches the nearest target range boundary, the fluid statusis more likely to remain within the target range longer and more optimalresults can be expected.

If the target level has not been reached, as determined at block 216,the control parameter may be adjusted at block 218 based on a comparisonof an updated fluid status measurement and the target range. Forexample, if the updated measurement obtained after startingultrafiltration has dropped from exceeding a high threshold orpercentile to a medium threshold or percentile, the ultrafiltration flowrate may be reduced from a high rate to a medium rate at block 218.

Ultrafiltration is continued at block 220 using the adjusted controlparameter, and fluid status continues to be monitored at block 214. Ifthe target range is reached at block 216 (i.e., a nearest boundary ofthe target range is reached) but a target level within the target rangehas not yet been reached, the ultrafiltration control parameter may bereduced to a lowest setting at block 218 until the target level isreached. As such, in one embodiment, the ultrafiltration therapy can bedescribed as being delivered with a hysteresis where stopping theultrafiltration therapy lags the fluid status measurement reaching atarget range by the time it takes to reach a target level within thetarget range or until the fluid status measurement has remained withinthe target range for some minimum period of time.

In the illustrative embodiment described, the control parameter of flowrate has been described as having three hierarchical settings, low,medium and high, which would be adjusted based on hierarchicalthresholds applied to a fluid status measurement. However it isrecognized that any number of settings may be applied to a controlparameter based on multiple threshold levels applied to the fluid statusmeasurement. Furthermore, continuous smooth adjustment of flow rate iscontemplated as the fluid status measurement continuously improvesduring the ultrafiltration therapy. In other words, as the fluid statusmeasurement continuously trends toward the target range, theultrafiltration flow rate may be continuously decreased, or decreased insmall stepwise increments, as the fluid status measurement improves.

FIG. 5 is a time-based plot 300 illustrating a fluid status measurementas it might vary over the course of periodic ultrafiltration therapysessions. A fluid status measurement 302 increases over time leading upto each periodic ultrafiltration therapy session 304 a, 304 b and 304 c,also referred to collectively as sessions 304. Ultrafiltration therapysessions 304 may be performed on a scheduled basis, for example, weekly,every three days, or another prescribed frequency. During theultrafiltration therapy sessions 304, the fluid status measurement 302is seen to decrease below an upper boundary 306 of a target range 310.Ultrafiltration is continued until the fluid status measurement 302reaches a lower boundary 308 of the target range 310.

In this illustrative example, the fluid status measurement maycorrespond to, without limitation, right ventricular systolic pressure,right ventricular diastolic pressure, or ePAD pressure. Target rangesfor these measurements will likely vary between patients but may be, forexample, approximately 20 to 25 mmHg for right ventricular systolicpressure, approximately 2 to 3 mmHg for right ventricular diastolicpressure, and approximately 10 to 12 mmHg for ePAD pressure.Ultrafiltration therapy is indicated when the patient's fluid statusmeasurement exceeds the target range and may be delivered until themeasurement reaches the lower boundary of the target range.

FIG. 6 is a time-based plot 350 illustrating changes that may occur in afluid status measurement 360 during an ultrafiltration therapy session.In this example, the fluid status measurement 360 again corresponds to apressure measurement though other fluid status measurements may besimilarly monitored and may exhibit an increasing or decreasing trend asultrafiltration therapy is delivered and the patient's fluid statusimproves.

The ultrafiltration therapy is started at 352 at an initially high flowrate 370. When the fluid status measurement 360 crosses a firstthreshold 362, defining the boundary of a high flow rate zone of thefluid status measurement 360, the ultrafiltration flow rate is adjustedto a relatively slower flow rate 372. Ultrafiltration is delivered atthe flow rate 372 for an interval of time until the fluid statusmeasurement 360 crosses a next, lower threshold 364. Upon reaching thenext lower threshold 364, the flow rate is again decreased to a rate 373until the fluid status measurement reaches the upper boundary 306 oftarget range 310. The upper boundary 306 is the nearest boundary to theinitial fluid status measurement at the time ultrafiltration was startedand the lower boundary 308 is the furthest boundary relative to theinitial fluid status measurement.

Ultrafiltration continues at the lowest flow rate 374 after crossing thenearest (upper) boundary 306 until the furthest (lower) boundary 308 oftarget range 310 is reached. The changes in the flow rate areaccompanied by a change in the slope of the fluid status measurement 360as can be seen in FIG. 6. It is recognized that depending the fluidstatus measurement being used, a change in slope in the measurement maylag the change in the ultrafiltration control parameter. Methodsdescribed herein relate to adjusting an ultrafiltration flow ratehowever other ultrafiltration control parameters may be adjusted such aspressure across the ultrafiltration membrane.

FIG. 7 is a flow chart 400 of an alternative method for regulatingultrafiltration therapy. At block 402, a physiological signal is sensedand used to compute fluid status measurements acquired and stored atblock 404. A target range corresponding to an optivolemic range of thefluid status measurement is computed automatically at block 406 usinghistorical trends of the measurement. For example, a range in which aspecified percentage of the fluid status measurements fall may becomputed. To illustrate, a range in which approximately 80% of the fluidstatus measurements fall may be determined. In other words, a range inwhich the patient remains for a specified percentage of time may beidentified. Alternatively, a distribution of the fluid statusmeasurements may be determined and a percentile range of thatdistribution may be defined as the target range. In still otherembodiments, a range may be defined relative to a mean or median value,averaged minimum or maximum measurements, or other feature of thehistorical data or any combination thereof.

In the absence of a historical trend in a given patient, e.g., soonafter implant of the IMD, population-based values for an initial ordefault range of a given fluid status measurement may be used forsetting a target range. If the IMD has acquired short term data, forexample one day, rather than days or months of data, this short termdata may be evaluated relative to the population based estimates for atarget range to then determine initial control settings for the patientfor an ultrafiltration episode. The ultrafiltration system could then“learn” the patient's target range as more, longer term data becomesavailable for that patient.

At block 408, the current fluid status measurement is compared to atherapy threshold. The threshold for indicating a need forultrafiltration therapy may be a boundary of the target range or a valueoutside the target range. If the therapy threshold is not crossed, fluidstatus measurements continue to be acquired and stored. The target rangemay be automatically updated periodically using recent data.

If the therapy threshold is crossed, a notification may optionally begenerated at block 412 by the IMD or other system component detectingthe therapy threshold crossing. For example, a notification may begenerated by the IMD and transmitted to an external programmer, homemonitor or centralized database to notify the patient and/or a clinicianor emergency responder of a need to initiate therapy or that the therapyis being initiated automatically. In some embodiments, the therapy willbe initiated manually in response to an automatic determination of theneed for therapy. In other embodiments, the therapy will be initiatedautomatically by a controller in response to the IMD (or other systemcomponent) detecting a therapy threshold crossing.

At block 410, the controller establishes a control parameter settingusing the current value of the fluid status measurement. In someembodiments, the control parameter may be an on/off setting whichenables or disables ultrafiltration automatically based on the fluidstatus measurement crossing a therapy threshold. If the ultrafiltrationunit is embodied as an implantable device, ultrafiltration isautomatically started in response to the therapy threshold crossing.

In other embodiments, other control parameters may be established, suchas a flow rate, which may be established based on a valve setting orother mechanism that controls the rate of blood flowing through theultrafiltration unit. For example, a valve may be controlled to be fullyopen (high flow rate), partially closed (low full rate), or fully closed(off).

The ultrafiltration therapy is started at block 414 using theestablished control parameter setting(s). As described previously, thefluid status measurement is monitored during ultrafiltration at block416 to allow further adjustment of a control parameter at block 420 asneeded and to determine when a target level of the fluid statusmeasurement is reached at block 418. Ultrafiltration continues at block422 until the target level is reached at block 418, at which timeultrafiltration is stopped at block 424. The IMD continues to acquireand store fluid status measurements at block 404 to determine whenultrafiltration therapy is needed again.

Initially following an ultrafiltration session, the fluid statusmonitoring may be performed at block 404 in an acute mode in which fluidstatus measurements are obtained more frequently than in a chronicmonitoring mode. The acute mode may be sustained for a specified periodof time, for example, several hours or days. A notification isoptionally generated at block 426 to notify the patient and/or aclinician that a target level has been reached and that ultrafiltrationtherapy has been or is being stopped.

As such, a fully automated, closed-loop method of regulatingultrafiltration therapy is contemplated in which the IMD (or othersystem component receiving IMD fluid status measurements) determines,based on fluid status measurements, when ultrafiltration needs to bestarted and stopped. A controller may further use the fluid statusmeasurements to establish and automatically set ultrafiltration controlparameters. It is recognized that in various embodiments, semi-automatedmethods may be implemented in which user-intervention is required, e.g.to enable data transmission, to enable an ultrafiltration unit to startoperating, to set an established control parameter, to disable or stopthe ultrafiltration unit operation, or the like.

After stopping ultrafiltration, the therapy session may be logged atblock 428 by the IMD, a programmer, in the central database or by theultrafiltration unit. The start and stop times and dates, controlparameters used during therapy delivery and fluid status measurementsobtained leading up to, during and after ultrafiltration therapy may bestored by the IMD or another system memory to provide diagnostic andprognostic data to a clinician for managing the patient. Such data maybe used in setting the fluid status measurement target range, targetlevel, therapy threshold (if different than a target range boundary),and in establishing ultrafiltration control parameters. Such datastorage may further include documentation of patient symptoms to allowindication of fluid overload or volume depletion (for example byover-diuresis) to be correlated to the fluid status measurements andcontrol parameters. This information may be used by the clinician or bythe medical device system automatically to adjust a therapy threshold,target level, target range or control parameters, for example, if thepatient shows signs of hypovolemia subsequent to the ultrafiltrationtherapy, if the frequency of ultrafiltration therapy is high due toearly crossing of a therapy delivery threshold after ultrafiltrationtherapy, or if the patient experiences hypervolemic symptoms earlierthan expected after ultrafiltration.

Thus, methods and associated apparatus for regulating ultrafiltrationtherapy have been presented in the foregoing description with referenceto specific embodiments. It is appreciated that various modifications tothe referenced embodiments may be made without departing from the scopeof the invention as set forth in the following claims.

What is claimed is:
 1. A medical monitoring system, comprising: animplantable medical device comprising one or more sensors for sensing atleast two different physiological signals in a patient; a processorconfigured to receive the physiological signals and compute at least twodifferent fluid status measurements of the patient using each of the atleast two different physiological signals; wherein at least one of thephysiological signals is an ECG signal; an external therapy deliverydevice for delivering ultrafiltration therapy to the patient accordingto a therapy delivery control parameter; and a controller configured toreceive the at least two different fluid status measurements andestablish a setting for the control parameter in response to the fluidstatus measurements; a memory storing a target range of the fluid statusmeasurements, wherein the target range is an index computed using acombination of the at least two different fluid status measurements; thecontroller further configured to compare each of the fluid statusmeasurements to the target range and automatically establish the controlparameter in response to the comparison that readjusts anultrafiltration level or an ultrafiltration pump flow rate.
 2. Thesystem of claim 1 wherein the processor is further configured todetermine a trend of previously computed fluid status measurements andcompute the target range using the trend.
 3. The system of claim 1wherein the control parameter corresponds to a flow rate and thecontroller is further configured to establish the control parameter inproportion to a difference between the fluid status measurements and thetarget range.
 4. The system of claim 1 wherein the memory storing atarget level of the fluid status measurements, the processor, thecontroller and the ultrafiltration therapy delivery device configured tooperate cooperatively to perform ultrafiltration until a current fluidstatus measurement reaches the target level.
 5. The system of claim 1further comprising a memory storing a therapy delivery threshold; theprocessor further configured to compare the fluid status measurement tothe therapy delivery threshold and detect a need for ultrafiltrationtherapy in response to the comparison; the controller being furtherconfigured to enable the ultrafiltration therapy delivery device inresponse to detecting the need.
 6. The system of claim 1 wherein thecontroller is further configured to receive an updated fluid statusmeasurement during delivery of ultrafiltration therapy and to determinean adjusted setting for the control parameter in response to the updatedfluid status measurement.
 7. The system of claim 1 wherein thecontroller is an implantable unit and the controller and the therapydelivery device are configured for wireless communication.
 8. The systemof claim 1 wherein the implantable medical device further comprises atelemetry module and the processor is an implantable processorimplemented in the implantable medical device; the controller being anexternal device in bidirectional telemetric communication with theimplantable medical device.
 9. The system of claim 1 further comprisinga memory for logging an ultrafiltration therapy session delivered by thetherapy delivery device according to the established control parameter.10. The system of claim 1, wherein the external therapy delivery devicedelivers therapy to a therapy delivery threshold based on comparing thefluid status measurement to the therapy delivery threshold.
 11. Thesystem of claim 10, wherein the implantable sensor detects a need forultrafiltration therapy in response to the comparison and enables thetherapy delivery device in response to detecting the need.
 12. Thesystem of claim 1, wherein the processor is configured to receive thephysiological signals and compute at least two volume statusmeasurements of the patient using each of the at least two differentphysiological signals; and the controller configured to receive the atleast two volume status measurements and establish a setting for thecontrol parameter in response to the volume status measurements; amemory storing a target range of the volume status measurements, whereinthe target range is an index computed using a combination of the atleast two volume status measurements; the controller further configuredto compare each of the volume status measurements to the target rangeand automatically establish the control parameter in response to thecomparison.
 13. The system of claim 12 wherein at least one of the atleast two different physiological signals are selected from the groupconsisting of intraventricular pressure, thoracic impedance, oxygen,blood urea nitrogen, serum creatine, serum electrolytes, blood glucose,thyroid stimulating hormone, or any combination thereof.
 14. The systemof claim 1 wherein the at least two different physiological signalsinclude at least one signal selected from the group consisting ofintracardiac right ventricular pressure signals, and transthoracicsignals.
 15. The system of claim 1, wherein the processor is configuredto receive the physiological signals and compute at least one volumestatus measurement of the patient and at least one fluid statusmeasurement of the patient using each of the at least two physiologicalsignals; and the controller configured to receive the at least one fluidstatus measurement and at least one volume status measurement andestablish a setting for the control parameter in response to the fluidstatus measurement and the volume status measurement; a memory storing atarget range of the fluid status measurement and the volume statusmeasurement, wherein the target range is an index computed using acombination of the at least one fluid status measurement and at leastone volume status measurement; the controller further configured tocompare each of the fluid status measurement and the volume statusmeasurement to the target range and automatically establish the controlparameter in response to the comparison.
 16. The system of claim 1further comprising a display unit to show either the fluid statusmeasurements, the difference between the fluid status measurements andthe target range, or both.
 17. The system of claim 1 further comprisingan audio or visual alert if a fluid status measurement differs from thetarget range by a predetermined amount.
 18. A medical monitoring system,comprising: an implantable medical device comprising a sensor sensing atleast two different physiological signals in a patient; a processorconfigured to receive each of the physiological signals and compute atleast two different fluid status measurement of the patient using eachof the at least two different physiological signals; wherein at leastone of the physiological signals is an ECG signal; an external therapydelivery device for delivering ultrafiltration therapy to the patientaccording to a therapy delivery control parameter; and a controllerconfigured to receive the at least two different fluid statusmeasurements and establish a setting for the control parameter inresponse to the fluid status measurements wherein the processor isfurther configured to determine a trend of previously computed fluidstatus measurements and compute the target range using the trend,wherein the target range is an index computed using a combination of theat least two different fluid status measurements; that readjusts anultrafiltration level or an ultrafiltration pump flow rate.
 19. Amedical monitoring system, comprising: an implantable medical devicecomprising one or more sensors for sensing a transthoracic impedancesignal in a patient, and at least one other physiological signal; aprocessor configured to receive the transthoracic impedance signal andthe at least one other physiological signal and compute a fluid statusmeasurement of the patient using the transthoracic impedance signal andthe at least one other physiological signal; wherein the at least oneother physiological signal comprises an ECG signal; a therapy deliverydevice for delivering ultrafiltration therapy to the patient accordingto a therapy delivery control parameter; and a controller configured toreceive the fluid status measurement and establish a setting for thecontrol parameter in response to the fluid status measurement; thatreadjusts an ultrafiltration level or an ultrafiltration pump flow rate.20. A medical monitoring system, comprising: an implantable medicaldevice comprising one or more electrodes for sensing at least twodifferent physiological signals in a patient; a processor configured toreceive the physiological signals and compute at least two differentfluid status measurements of the patient using the at least twodifferent physiological signals; wherein at least one of thephysiological signals is an ECG signal; an external therapy device fordelivering ultrafiltration therapy to the patient according to a therapydelivery control parameter; a memory storing a target range of the fluidstatus measurement, wherein the target range is an index computed usinga combination of the at least two different fluid status measurements; acontroller configured to receive the fluid status measurements andestablish a setting for the control parameter in response to the fluidstatus measurements, the controller further configured to compare thefluid status measurements to the target range and adjust the controlparameter in response to the comparison during a closed loop operation;that readjusts an ultrafiltration level or an ultrafiltration pump flowrate.